HIV-1 infection poses a public health problem that is partially controlled by a combination of specific antiretroviral agents that targets viral proteins. Nonetheless, the surge of multi-resistant HIV-1 strains will require the development of novel antiviral strategies. The search of new anti-retroviral compounds that affect viral-cellular interfaces represents a new challenge to provide new therapies that could alternate HAART therapy and reduce the emergence of HIV-1 resistant strains. During all the steps of HIV-1 replication in the main target cells (activated CD4 T cells and macrophages) the virus takes advantages of the functions of cellular proteins to accomplish its infection or to hide its replication from the immune system response [1-4].
Numerous cellular proteins that promote HIV-1 infection have been identified either by wide throughout screening or by single studies that decipher the role of each factor in viral entry, uncoating, reverse transcription, nuclear import, integration, transcription, viral RNA export and translation, assembly and budding [5-8]. Host proteins have been involved in the virological synapse formation and in the cell-to-cell-transmission of HIV-1, which is the most efficient mode of viral dissemination [9, 10]. Nevertheless, most of the identified HIV-1 cellular co-factors have been discovered using epithelial cell based in vitro systems that do not express endogenously HIV-1 receptor (CD4) and co-receptors (CCR5 and CXCR4), and do not have the same biology of macrophages and activated CD4 T cells. The use of CD4+ T cell lines and monocytic cell lines improved the field in validating the role of the identified cellular proteins in HIV-1 replication. However, the big issues remain the validation of the roles of these cellular factors on in vitro differentiated primary macrophages or activated CD4 T cells and during in vivo (acute and chronic) HIV-1 infections.
The identification of molecular mechanisms by which HIV-1 uses the host proteins to accomplish efficiently its replication is required for the design of novel drugs that are able to target specifically viral-cellular interfaces and inhibit the infection. This strategy will—with no doubt—avoid the emergence of viral resistance strains after anti-retroviral therapies using drugs that target directly the HIV-1 proteins. For example, LEDGIN peptides abolish the protein-protein interaction between LEDGF/p75 and HIV-1 integrase. These peptides strongly inhibit HIV-1 replication by avoiding the tethering of HIV-1 pre-integration complex to the chromatin of host genome by LEDGF/p75 and by reducing the viral integrase catalytic activity [11].